The present invention concerns heterocyclic carbon compounds comprising 4-phenyl-1,4-dihydropyridines having various aminoalkyl moieties connected via a cyanoguanidine group to the 3-position of the 4-phenyl ring. These compounds are NPY antagonists.
A substantial body of art has accumulated over the past two decades with respect to the 4-aryl-1,4-dihydropyridine class of compounds. Syntheses of compounds in this category have been driven by their pharmacologic actions involving calcium channels rendering them useful for treating cardiovascular disorders such as ischemia and hypertension.
U.S. Pat. No. 4,829,076 to Szilagyi, et al. is an example of such substituted dihydropyridine derivatives, disclosing and claiming inter alia compounds of formula (1) as calcium antagonists for treating hypertension. ##STR2##
The closest art would be our previous work involving 4-(3-substituted-phenyl)-1,4-dihydropyridine derivatives having NPY antagonist properties. These derivatives conform to structural formula ##STR3##
In (2) B is either a covalent bond or the group --NH--. The symbol Z denotes hetaryl moieties, examples being piperidine or piperazine.
In U.S. Pat. No. 5,554,621, Z is a fused ring or spiro-fused nitrogen heterocycle. In U.S. Ser. No. 482,355, Z is a piperazinyl or homopiperazinyl moiety. Z is a piperidinyl or tetrahydropyridinyl moiety in U.S. Ser. No. 639,968.
These reference compounds are easily distinguished from the compounds of the instant invention by virtue of the linking functional groups. The cyanoguanidine linking moiety is a novel structural feature in the new compounds, connecting the side-chain to the 4-phenyl ring. A cyanoguanidine moiety has previously appeared in a different location in 4-phenyl-1,4-dihydropyridine derivatives.
Alker, et al. in J. Med. Chem., 1990, 33, 585-591 disclosed, inter alia, compounds of formula (3) having calcium antagonism activity. ##STR4## As can be seen, these compounds differ structurally from the compounds of the present invention.
In summary, the prior art does not disclose nor suggest the unique combination of structural fragments which embody these novel dihydropyridine derivatives which possess good antagonist activity at NPY Y.sub.1 receptor sites while having reduced cardiovascular effects.